Cyclopentano-phenanthrene compounds



2,759,952 CYCLOPENTANU PHENANTIHtENE CDMPOUNDS Max N. Huhman, Oklahoma City, Lasdon Foundation, line, Yonkers, tion of Delaware 0111a,, assignor to N. Y., a corpora- No Drawing. Application August 1,

Serial No. 525,801

13 Claims. cl. 260 s97. s

This invention relates to certain novel compounds of the androstene series, and relates more particularly to the novel compounds A -androsten-3/9,16,8-diol and A -androsten-3,6,l6a-diol and to the ethers and esters of said compounds.

An object of this invention is the preparation of compounds of the androstene series having diminished or minimal hormonal activity but which exhibit other useful physiological action.

of hormonally active compounds are known. Some are found in nature. thers have not been isolated from nat ural sources but are formed by chemical alteration of the known compounds. For example, A -androsten- 3p,l7 8-diol is a urinary steroid which has been identified as a metabolic product associated with adrenal dysfunction. Naturally-occurring stereo or structural isomers of this compound are, however, unknown.

In accordance with my invention, I have found that by suitable chemical alteration of the molecular configuration of A -androsten-3/i,17B-diol, valuable structural isomers of this steroid are obtained of androgenic activity, are highly elfective in hypertensive states. The novel steroid compounds of my invention exert a strong hypotensive action on oral administration and have been observed to eifectively reduce blood pressure in hypertensive states.

The novel steroid compounds of my invention comprise A -androsten-3B,l6B-diol and A -androsten-3fl,16adiol, and the functional derivatives of these novel compounds including the ethers and esters. More particularly, the compounds of my invention may be represented by the following general formula:

CH CH3 wherein X is selected from the group consisting of hydrogen and -R and in which R is a monovalent radical of the group consisting of methyl, ethyl, propyl, butyl, amyl, vinyl, cyclopentylpropyl, acetyl, propionyl, butyryl, cyclopentylpropionyl, benzoyl, palmityl, benzyl, tolyl, and naphthyl groups.

atent ii which, although free Patented Aug. 21, 1%56 ice The particular species of my invention comprising A androsten-3fl,16fl-diol may be obtained, for example, by converting dehydroepiandrosterone to M-androsten-S/i-oll6-one, in accordance with the process more particularly described in my copending application S. No, 591,210 filed on April 13, 1955, and then reducing the A -andr0- sten-3p-ol-l6-one obtained. Conveniently, a reducing agent such as sodium borohydride, lithium aluminum hydride or lithium borohydride may be employed.

The process of converting dehydroepiandrosterone to A -andr0sten-3B-ol-l6-one comprises nitrosating the 17- the former with isoamyl. nitrite and potassium t-butoxide in t-butyl alcohol, and subjecting the l6-oximino-l7-keto compound obtained to a Stodola reduction with zinc dust and acetic acid to form the corresponding 16-keto-17-hydroxy compound. The latter is reacted with an aryl sulfonyl chloride, such as benzene sulfonyl chloride or p-toluene sul'fonyl chloride to form the l6-keto-l7-aryl sulfonate and the l6-keto group reduced to a l6-hydroxy group with a reducing agent such as sodium borohydride, lithium aluminum hydride or lithium borohydride, for example. On reaction of the 16-hydroxy-l7-aryl sulfonate with an alkali metal hydroxide, the aryl sulfonic acid is split out, yielding A -androsten- 3B-ol-16-one with the l7-position being free of any functional group.

The stereo isomer A -androsten-3fi,16u-dio1 may be ob tained by epimerizing A -androsten-3fi,16B-diol. This reaction comprises forming the di-tosylate of A -androsten- 35,16 3-di0l by reaction with p-toluene sulfonyl chloride followed by selective hydrolysis of the ester at C3 to yield the free hydroxy group. Epimerization at C1s by reaction of the A -androsten-3p,16,9-diol-16-p-toluene sulfonate with sodium acetate in acetic acid forms A -androsten- 3B,l6n-dioi-l6-acetate and hydrolysis of the latter yields the isomer A -andrOsten-3fi,l6uz-di0l.

Alternatively, A -androsten-3/3,IGa-diol may be obtained by esterifying A -androsten-3fi-ol-l6-one with acetic anhydride to block the C3 hydroxy group and to form Sfl-acetoxy-M-androsten-l6-one followed by the reducgroup to yield 3fi-acetoxy-A -androsten-l6fi-ol. The latter compound is then reacted with ptoluene sulfonyl chloride to form the C16-p-toluene sulfonate which is epimerized as described above by the acetate exchange reaction to form Sfl-acetoxy-l6a-acetoxy-A -androstene and the dracetate then hydrolyzed to A 'andro- The novel compounds of my invention may also be obtained utilizing a C3 ether of A -androsten-3B-ol-l6-0ne as the starting material. The desired ether may be obtained utilizing an etherifying agent such as dimethyl sulfate, diethyl sulfate, dibenzyl sulfate and the like. Thus, I may start with the 3-methyl, 3-efl1yl, S-propyl, 3-butyl, 3-isoamyl, S-amyl, 3-vinyl, 3-cyclopentylpropyl, 3-benzyl, 3- tolyl, and 3-naphthyl ether of said A -androsten-3fi-ol-l6- one, subject the l6-keto group of the latter to reduction, as described, to form the acid to form the 16a-acetoxy hydrolysis yields A -androsten-3p- The free hydroxy group may be etherified tion from 80% aqueous methanol.

illustrate my invention but without the following examples are given:

In order further to being limited thereto,

Example I To 1.0 grams of A -androsten-3p-ol-16-one in 50 ml. of

V methanol are added a solution of 0.8 grams of sodium Percent Percent O H Calculated 78. 57 10. 41 Found 78. 70 10. 34

/ The optical rotation is [a] =-61 (c==l.l in 95% ethanol).

Example 11 99 mg. of A -androsten-3fl,16p-diol melting at 145- 145.5 C. are dissolved in about parts by weight of dry pyridine and about 10 parts by weight of acetic anhydride are added. After mixing thoroughly and permitting the mixture to stand for 24 hours at about 25 C., about 500 parts by weight of ice water are added to precipitate the A -androsten-3fi,l6fi-diol-di-acetate. The product is filtered oil and purified by recrystalliza- The product forms fiat, silky needles melting at 127.5l28 C. A yield of 98 mg. is obtained. Analysis for C23H34O4 is:

Percent Percent O H Calculated 73. 76 9. Found 73. 96 9.19

The optical rotation is [a] =-65 (c=1.04 in chloroform).

Example III A -androsten-3BJ6B-di0l is converted to A -androsten- 313,16fi-diol-di-benzoate by dissolving 130 mg. of the A andr0sten-3B,l6/3-diol in 6.0 ml. of pyridine containing 1.5 ml. of benzoyl chloride.The reaction mixture is maintained at room temperature for 24 hours and the dibenzoate formed is precipitated by adding 100 m1. of

ice water. The product is purified by recrystallizing several times from 95% aqueous ethanol. A yield of 155 mg. of A -androsten-3B,16,8-diol-di-benzoate in the form of fine, silky needles melting at l93l93.5 C. is obtained. Analysis for C33H3804 is:

Percent Percent Calculated 79. 48 7. 68 Found 79. 65 7. 70

Example IV 813 mg. of A -androsten-3B,165-diol are added to a solution of 6 grams of p-toluene sulfonyl chloride in 18 ml. of pyridine while maintaining the reaction mixture at 0 C. The mixture is thoroughly agitated and permitted to stand with the temperature gradually rising to room temperature. After remaining at room temperature for 24 hours, ice water is slowly added to the reaction mixture to precipitate the A -andr0Sten-3p, l613- diol-di-p-toluene sulfonate. The product is filtered, Washed with water and dried and is then dissolved in 82 ml. of alcohol-free acetone to which is added 27 ml. of water containing about 0.2 grams of sulfuric acid. The resulting acidic solution is refluxed for 4 hours, additional water is introduced and the volume reduced by distillation until the clear solution becomes turbid. This selective hydrolysis forms 365 mg. of A -androsten- 3/3,16fl-diol-l6-p-toluene sulfonate which is purified by recrystallization from aqueous acetone containing decolorizing carbon. The latter compound melts at 91- 96 C. Analysis for C26H3604S is:

Percent S Calculated 7.21 Found 6.99

330 mg. of the above 16-p-toluene sulfonate are epimerized by adding the latter to 16 ml. of purified acetic acid containing.0.8 gram of freshly fused sodium acetate and heating the mixture under reflux for one hour. The A -androsten-3p,16a-diol-16-acetate formed is separated by cooling the reaction mixture and precipitating the compound by the addition of 250 ml. of ice water. After the mixture containing the precipitate is maintained at about 5 C. for 24 hours, the product is filtered olf and dried. In order to obtain the free A -androsten-3fi,l6ot-diol, the ester is saponified by adding the product to a solution of 100 ml. of methanol, and 19 ml. of sodium hydroxide solution containing 1.9 grams of sodium hydroxide and allowing the mixture to stand for 24 hours at room temperature. The alkaline mixture is then shaken in a separatory funnel with a mixture of ethyl ether and dilute aqueous sodium hydroxide so that the ethyl ether preferentially extracts the steroid material. The ether is separated, washed with dilute aqueous sodium hydroxide and then with water. After removal of the ether the residue is recrystallized twice from a mixture of acetone-Skellysolve B and then twice from aqueous methanol. A yield of 74 mg. of A -androsten-3B,l6a-diol is obtained melting at 213- 214 C. Analysis for C19H30O2 is:

The optical rotation is [a] =-1lO (c=1.09 in ethanol).

Example V 992 mg. of A -andrOsten-Bfl-ol-16-one melting at 162- 163 C. is acetylated with acetic anhydride in pyridine and the SB-acetoxy-M-androsten-l6-one formed is separated by precipitating it from solution by the addition of Water. After drying, the acetate thus separated is dissolved in 80 ml. of ethyl acetate and a solution of 8/10 grams of sodium borohydride in 80 ml. of ethanol added and after thorough mixing, the solution allowed to stand for 15 minutes at room temperature. Ice water is added to precipitate the 3/3-acetoxy-A -androsten-16p- 01 which is then filtered off, washed well with water and dried at 40 C. The product is then added to a solution of 2 grams of p-toluene sulfonyl chloride in 20 ml. of pyridine and the mixture allowed to stand for minutes at 0 C. and for 24 hours at 25 C. The A androsten 35,165 diol 3 acetate 16 p toluenesulfonate is precipitated from solution by the addition of ice water and the product then filtered off, washed with water and dried. The product is then epimerized at C16 to yield A -androsten-3fi,l6a-diol-di-acetate by adding it to a solution of 3.2 grams of freshly fused sodium acetate in 64 ml. of purified acetic acid and heating it under reflux for one hour, and then precipitating with much ice water.

.The ester thus formed is saponified by adding it to a solution of 8 parts by weight of sodium hydroxide in 80 parts by Weight of Water containing 240 parts by weight of methanol and maintaining the resulting solution at room temperature for about 24 hours. The alkaline reaction mixture is partitioned by shaking washed twice with then washed thoroughly with water. from the alkali and Water washes is thoroughly extracted methanol. of theory of A -androsten-3/8,16a-diol is obtained melting at 213.5- 214.5 C.

Example VI Percent Percent The optical rotation is [a] =-88 (:107 in chloroform).

Example VII M-androsten-Sfi,16a-diol-di-benzoate is obtained by reacting A -androsten-3p,l6a-diol with benzoyl chloride in pyridine. The di-benzoate formed is recrystalled from 95% aqueous ethanol and is found to have a melting point of 180-181 C. Analysis for CasHssOa. is: MN

Percent Percent Example VIII 978 mg. of 3B-met h0Xy-A andr0sten-l6-0ne melting at l-l36 C. is reduced by reacting it with a solution of 0.8 grams of sodium borohydride in ml. methanol at room temperature for 30 minutes. The 3fi-methoxy- A androsten 465-01 is adding water to being made as Percent Percent Calculated 78. 89 10. 59

oun. IIII:IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII 79.02

The optical rotation is [a] =-70 (c=l.05 in aqueous ethanol).

Example IX Percent Percent O H Calculated Z8. 23 i8. 2?

8. Found 7a. 7.7 10.56

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of my invention.

Having described my invention, what I desire to secure by Letters Patent is:

l. The steroid compounds of the formula:

CH3 CH3 of hydrogen and radical of the group butyl, amyl, vinyl, propionyl, butyryl, cyclobenzyl, benzoyl, tolyl and consisting of methyl, ethyl, propyl, cyclopentylpropyl, acetyl, pentylpropionyl, palmityl, naphthyl groups.

2. The steroid compound A -androsten-35,16 3-diol.

3. The steroid compound A -androsten-3fi,16m-dioi.

4. The steroid compound A -androsten-3B,l6fl-diol diacetate.

5. The steroid -01. 7

6. The steroid compound 3/3-methoxy-A -androstenl 605-01-16-36'6'E2tt.

7. The steroid compound A -androsten-3 3,ldot-diol diacetate.

8. The steroid compound l6zx-Ol.

9. Process for the preparation of A -androsten-3/3,16 8- diol which comprises reducing A -androsten-3fl-0l-16-one.

10. Process for the preparation of a 3-ether of A androsten-3fl-16m-diol which comprises reacting A -androsten-3fi-ol-16-one with an etherifying agent to form a B-ether of M-androsten-Bfl-ol-l6-one, reducing said compound to yield a B-ether of A -androsten-3/3,l6;3-diol, reacting the hydroxy compound with an aryl sulfonyl halide to form a A -androsten-3fi,l6fi-diol-3fl-ether-16fiaryl sulfonate, reacting the aryl sulfonic acid ester thus obtained with an alkali metal acetate and acetic acid to form a A -androsten-3fi,l6ct-diol-3fl-ether-16a-acetate and hydrolyzing said compound to form a S-ether of A -androsten-3fi,l6u-diol.

11. Process for the preparation or" A -androsten-3B,16mdiol Which comprises esterifying M-androsten-BBJGB- diol to form a A -androsten-3/3,16fl-diol-di-arylsulfonate, selectively hydrolyzing said di-arylsulfonate to form. the A -androsten-3B,16p-diol-lG-arylsulfonate, reacting said A -androsten-3fl,16,8-diol-l6-arylsulfonate with an alkali compound 3fl-methoxy-A -androsten 3,6-methoxy-A -androsten- -7 7 metal acetate in acetic acid to epimerize said compound and to form A -androsten-3fi,16u-dio116-acetate, and then hydrolyzing the latter to yield A -androsten-3p,16mdiol.

12. Process for the preparation of A -androsten-3fl, 16u-diol, which comprises esterifying A -androsten-wo1-16-one to form a 3-ester of A -androsten-3 8-ol-16-one, reducing the 16-keto group, reacting the 3-ester of A androsten-EEBJGfl-diol obtained with an aryl sulfonyl halide and forming a M-androsten-Bfl,16fl-diol-3-ester- 16fl-ary1-sulfonate, reacting the latter with sodium acetate in acetic acid to epimerize said aryl sulfonate and 8 form a A -androsten-3p,16a-dio1-3p-ester-Mot-acetate and hydrolyzing said di-ester to the desired A -androsten- 35,16u-dl0l.

13. The p-toluene sulfonates of the group consisting of M-androsten-B/BJGB-diol di-(p-toluenesulfonate), A -androsten 35,165 diol 16 (p-toluenesulfonate), A androsten 313,165 diol 35 acetate 16p (p-toluenesulfonate) and 3p-meth0Xy-A -androsten-16fi-o1-16fl-(ptoluenesulfonate) No references cited. 

1. THE STEROID COMPOUNDS OF THE FORMULA: 